Imidazolidinone derivatives as central nervous system depressants

ABSTRACT

COMPOUNDS OF THE CLASS OF 1-(2- AND 3-(4-(10,11-DOHYDRO-5H-DIBENZO(A,D)CYCLOHEPTEN - 10 - YL) - 1 - PIPERAZINYL)-ALLYL) - 3 - ALKYL - 2 - IMIDAZOLIDINONE WHICH CAN BE SUBSTITUTED IN 8-POSITION BY CHLORO, METHYL OR METHOXY, AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, HAVE A DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM; PHARMACEUTICAL COMPOSITIONS COMPRISING THESE COMPOUNDS AND A METHOD OF PRODUCING A DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM OF WARM-BLOODED ANIMALS, ARE PROVIDED; AN ILLUSTRATIVE EMBODIMENT IS 1-(2-(4-(8METHYL-10,11-DIHYDRO - 5H - DIBENZO(A,D)CYCOLHEPTEN-10YL)-1-PIPERAZINYL)-ETHYL) - 3 - METHYL - 2 - IMIDAZOLIDINONE-BIS-MALEATE.

United States Patent IMTDAZOLIDINONE DERIVATIVES AS CENTRAL NERVOUSSYSTEM DEPRESSANTS Walter Schindler, Riehen, Basel-Land, and ArminZuest,

Birsfelden, Basel-Land, Switzerland, assignors to Ciba- GeigyCorporation, Ardsley, N.Y.

No Drawing. Original application Aug. 5, 1970, Ser. No. 61,435, nowPatent No. 3,720,676. Divided and this application Dec. 21, 1972, Ser.No. 317,341

Claims priority, application Switzerland, Aug. 11, 1969,

12,120/ 69 Int. Cl. A61k 27/00 US. Cl. 424-450 4 Claims ABSTRACT OF THEDISCLOSURE Compounds of the class of 1-[2- and3-[4-(10,11-dihydro-5Hdibenzo[a,d]cyclohepten yl) 1 piperazinyl]-allyl]3 alkyl 2 imidazolidinone which can be substituted in 8-position bychloro, methyl or methoxy, and the pharmaceutically acceptable acidaddition salts thereof, have a depressant efiect on the central nervoussystem; pharmaceutical compositions comprising these compounds and amethod of producing a depressant effect on the central nervous system ofwarm-blooded animals, are provided; an illustrative embodiment isl-[2-[4-(8- methyl-10,1l-dihydro 5H dibenzo[a,d]cyclohepten-lO-yl)-l-piperazinyH-ethyl] 3 methyl 2 imidazolidinone-bis-maleate.

DETAILED DESCRIPTION This is a division of application Ser. No. 61,435,filed Aug. 5, 1970, now US. Pat. 3,720,676. The present inventionrelates to new imidazolidinone derivatives, to processes for theirproduction, to pharmaceutical compositions comprising the new compounds,and to the use thereof.

More particularly, the invention relates to compounds of Formula I,

X is hydrogen, chloro, methyl or methoxy; R is alkyl having one to fourcarbon atoms; R is hydrogen or methyl; and

n is the integer 2 or 3;

and the pharmaceutically acceptable acid addition salts thereof.

It has now been found that such compounds, especially 1-[2-[4-(8-methyl10,11 dihydro 5H dibenzo[a,d] cyclohepten-lO-yl) 1piperazinyl1-ethyl]-3-methyl-2- imidazolidinone, and l-[2-[4-(8-chloro10,11 dihydro- 5H-dibenzo[a,d]cyclohepten-lO-yl) 1piperazinyH-ethyl]-3-methyl-Z-imidazolidinone, as well as theirpharmaceutically acceptable acid addition salts, possess valuablepharmacological properties, and a high therapeutic index. In the case oforal, rectal or parenteral administration, they have a centraldepressant action, e.g. they reduce motility, potentiate the efiect ofanaesthetics, have an antiemetic action, and have an inhibiting actionin the test de la traction. Furthermore, they have a sympathicolytic andserotonin-antagonistic action. These properties, which are determined bymeans of selected standard tests 3,798,325 Patented Mar. 19, 1974 ice R2(II) wherein X and R have the meaning given under Formula I, or analkali metal derivative of such a compound, with a reactive ester of acompound of Formula IH,

i (III) wherein R and n have the meaning given under Formula I; and,optionally, converting the reaction product with an inorganic or organicacid into an addition salt.

Suitable reactive esters of compounds of Formula HI are, e.g. halides,such as chlorides or bromides, also sulphonic acid esters, e.g. themethanesulphonic acid ester, or the 0- or p-toluenesulphonic acid ester.

These esters are reacted with the free bases II preferably in thepresence of a solvent. Suitable solvents are those which are inert underthe reaction conditions, e.g. hydrocarbons such as benzene, toluene orxylene; halogenated hydrocarbons such as chloroform; ethereal liquidssuch as ether or dioxane; as well as lower alkanones such as acetone,methyl ethyl ketone or diethyl ketone. The reaction temperatures arebetween ca. 50 and preferably at the boiling point of the appliedsolvent.

In the reaction according to the invention of one molecular equivalentof reaction ester with one molecular equivalent of free base, onemolecular equivalent of acid is split off. This acid can be bound toexcess base of Formula II, or to the dibasic reaction product. Anacidbinding agent is, however, preferably added to the reaction mixture.Suitable acid-binding agents are, e.g. alkali metal carbonates such assodium or potassium carbonate, also tertiary organic bases such as, e.g.pyridine, triethylamine or N,N-diisopropylethylamine. Excess tertiarybases may also be used as solvent.

If in the reaction according to the invention is used, instead of thefree base of Formula II, an alkali metal derivative thereof, e.g. asodium, potassium or lithium derivative, then it is advantageous for thereaction to be performed in a hydrocarbon, e.g. in benzene or toluene.

The formation of the alkali metal derivatives of the first reactant ispreferably performed in situ, e.g. by the addition of at least onemolecular equivalent of alkali metal hydride, alkali metal amide, or ofan alkali metal organic compound, when initially one molecularequivalent of free base is used. For example, sodium amide and lithiumamide are used as alkali metal amides; sodium hydride as alkali metalhydrides; and phenyl lithium or butyl lithium as alkali metal organiccompound.

Of the starting materials of Formula H, e.g 8-chloro- 1 l-piperazinyl)-1 0,1 l-dihydro-5H-dibenzo[a,d] cycloheptene is described in theliterature. 8-methyl-10-(1- piperazinyl) 10,11 dihydro 5Hdibenzo[a,d]cyc1oheptene can be obtained by another process, e.g. asfollows: Starting with 8-methyl-10-chloro-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene, this is condensed in benzene withl-piperazinecarboxylic acid ethyl ester to 4-(8-methyl- 10,11 dihydro 5Hdibenzo[a,d]cpclohepten-10-yl)- piperazine-l-carboxylic acid ethylester; the condensation product is subsequently hydrolysed anddecanboxylated by heating with potassium hydroxide in ethanol. Furtherstarting materials of Formula II can be produced analogously. The secondreactant of the process according to the invention are the reactiveesters of compounds of Formula III. Of these compounds, for example,1-(2- chloroethyl)- and l (3 chloropropyl) 3-methyl-2- imidazolidinoneas well as l-(2-chloroethyl)-3-butyl-2- imidazolidinone are known, andcan be produced by various processes. Further compounds of this type canbe produced analogously.

Using a second process according to the invention, compounds of FormulaI, of which the symbol n denotes 2, are obtained by reacting a compoundof Formula II, wherein X and R have the meaning given under Formula I,or an alkali metal derivative of such a compound, with a compound ofFormula IV,

3 H (IV) wherein Y represents halogen, and R; has the meaning givenunder Formula I,

or with an alkali metal derivative of such a compound; and, optionally,converting the reaction product with an inorganic or organic acid intoan addition salt.

As halogen, the radical Y of Formula IV is preferably chlorine orbromine.

The reaction according to the invention of the fi-ee bases of FormulaII, or of their alkali metal derivatives, with the urea derivatives, ortheir alkali metal derivatives, may be performed in the same solvents ordiluents, and at the same reaction temperatures, as in the firstprocess. In the reaction of one molecular equivalent of free base withone molecular equivalent of free urea derivative, two molecularequivalents of hydrogen halide are split off, which can also be bound tothe same acid-binding agents. Both reactants are used as alkali metalderivatives, e.g. as sodium, potassium or lithium derivatives,preferably in situ, in the process according to the invention. Thesealkali metal derivatives can be obtained analogously to the alkali metalderivatives of the first process.

The production of the starting materials of Formula II is describedfollowing the first process. A starting material which is embraced byFormula IV is 1-methyl-3,3- bis-(2-chloroethyl)-urea which can beobtained, e.g. starting with diethanolamine. With l-methylisocyanate,the diethanolamine yields 1 methyl 3,3-bis-(2-hydroxyethyl)- urea, whichreacts with thionyl chloride, whereby sulphur dioxide and hydrogenchloride are split off. Further starting materials of Formula IV can beproduced analogously.

Using a third process according to the invention, a reactive ester of acompound of Formula V,

gen

wherein X and R have the meaning given under Formula I, is reacted witha compound of Formula VI,

wherein R and n have the meaning given under Formula I, or with analkali metal derivative of such a compound; and, optionally, theobtained reaction product is converted with an inorganic or organic acidinto an addition salt.

Suitable reactive esters of compounds of Formula V are, e.g. halides,such as chlorides or bromides, also sulphonic acid esters such asmethane-sulphonic acid ester, 0- or ptoluenesulphonic acid ester, oro-chloroor p-chlorobenzenesulphonic acid ester.

The reaction according to the invention of the free bases, or of theiralkali metal derivatives, with the reactive esters can be performed inthe same solvents or diluents, and at the same reaction temperatures, asin the first process. With the reaction of one molecular equivalent offree base with one molecular equivalent of reactive ester, one molecularequivalent of acid is split off, which can be bound to the sameacid-binding agents as in the first process.

Instead of the free bases, it is also possible to use their alkali metalderivatives, e.g. sodium, potassium or lithium derivatives, preferablyin situ, in the process according to the invention. These alkali metalderivatives can be obtained analogously to the alkali metal derivativesin the first process.

Starting materials: reactive esters of compounds of Formula V, e.g. 8,10dihydro 5H dibenzo[a,d]cycloheptene, 8-methylor8-methoxy-l0-chloro-l0,1l-dihydro- SH-dibenzo[a,d]cycloheptene, aredescribed in the literature. Further starting materials of this type canbe produced analogously.

Furthermore, as representative of compounds of Formula VI are known,e.g. 1-[2-(l-piperazinyl)-ethyl]-3- methyl-Z-imidazolidinone, 1-[3 (1piperazinyl)-propyl]-3-methyl-2'imidazolidinone, as well as thecorresponding 3-ethyl-compounds; they can be produced by variousmethods. Further compounds of this type can be obtained analogously.

The compounds of Formula I obtained using a process according to theinvention are, optionally, subsequently converted, in the usual maner,into their addition salts with inorganic an organic acids. For example,to a solution of a compound of Formula I in an organic solvent is addedthe acid desired as salt component, or a solution of the acid.Preferably chosen for the reaction are organic solvents in which theformed salt is difiicultly soluble, so that it can be separated byfiltration. Such solvents are,

e.g. methanol, acetone, methyl ethyl ketone, acetone/ ethanol, methanol/ether or ethanol/ether.

It is possible to use as medicaments, instead of free bases,pharmaceutically acceptable acid addition salts, i.e. salts with suchacids of which the anions are not toxic in the case of the dosageamounts in question. It is moreover of advantage if the salts to be usedas medicaments crystallize well and are not, or only slightly,hygroscopic. For salt formation with compounds of Formula I it ispossible to use, e.g. hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,2-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid,citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelicacid and embonic acid.

As previously mentioned, the new active substances are administeredorally, rectally or parenterally. The dosage depends on the manner ofadministration, on the species, on the age, and on the individualcondition. The

daily dosages of the free bases, or of pharmaceutically acceptable saltsthereof, vary between 0.15 rug/kg. and 10.5 mg./kg. for warm-bloodedanimals. Suitable dosage units such as drages, tablets, suppositories orampoules, preferably contain 5-200 mg. of an active substance accordingto the invention.

Dosage units for oral administration contains as active substancepreferably between and 90% of a compound of Formula I or of apharmaceutically acceptable salt thereof. They are produced by combiningthe active substance, e.g. with solid pulverulent carriers such aslactose, saccharose, sorbitol, mannitol; starches such as potato starch,maize starch or amylopectin, also laminaria powder or citrus pulppowder; cellulose derivatives or gelatine, optionally with the additionof lubricants such as magnesium or calcium stearate, or polyethyleneglycols, to form tablets or drage cores. The drage cores are coated,e.g. with concentrated sugar solutions which can also contain, e.g. gumarabic, talcum and/ or titanium dioxide; or with a lacquer dissolved inreadily volatile organic solvents or mixtures of solvents. Dyestuffs canbe added to these coatings, e.g. to distinguish between varying dosagesof active substance.

Further dosage units suitable for oral administration are hard gelatinecapsules, as well as soft closed capsules made from gelatine and asoftener, such as glycerin. The hard capsules preferably contain theactive substance as a granulate, e.g. in admixture with fillers such asmaize starch, and/or lubricants such as talcum or magnesium stearate,and optionally stabilizers such as sodium metabisulphite (Na S O orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as liquid polyethyleneglycols, whereby stabilizers may also be added.

Suitable dosage units for rectal administration are, e.g. suppositoriesconsisting of a combination of an active substance with a suppositorybase material. Suitable suppository base materials are, e.g. natural orsynthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, orhigher alkanols. Also suitable are gelatine rectal capsules consistingof a combination of the active substance with a base material. Suitableas a base material are, e.g. liquid triglycerides, polyethylene glycols,or paraifin hydrocarbons.

Ampoules for parenteral administration, especially intramuscularadministration, preferably contain a watersoluble salt of an activesubstance in a concentration of preferably 0.55%, optionally togetherwith suitable stabilizers and buffer substances, in aqueous solution.

The following prescriptions further illustrate the production oftablets, drages, capsules, suppositories and ampoules:

(a) 250 g. of 1-[2-[4-(8-methyl10,1l-dihydro-SH-dibenzo[a,d]cyclohepten10 yl)-1-piperazinyl]-ethyl]-3- methyl-Z-imidazolidinone are mixed with175.80 g. of lactose and 169.70 g. of potato starch; the mixture is thenmoistened with an alcoholic solution of 10 g. of stearic acid, andgraulated through a sieve. After the granulate has dried, 160 g. ofpotato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g.of colloidal silicon dioxide are mixed in; the mixture is then pressedinto 10,000 tablets each weighing 100 mg. and each containing 25 mg. ofactive substance. These tablets can, if required be provided withgrooves for a more precise adjustment of the dosage amount.

(b) A granulate is produced fro 250 g. of 1-[2-[4-(8- chloro 10,11dihydro-5H-dibenzo[a,d] cyclohepten-10- yl) 1piperazinyl1-ethyl]-3-methyl-Z-imidazolidinone, 175.90 g. of lactose andthe alcoholic solution of 10 g. of stearic acid. After the granulate hasbeen dried, it is mixed with 56.60 g. of colloidal silicon dioxide, 165g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate;the mixture is then pressed into 10,000 drage cores. These aresubsequently coated with a concentrated syrup made from 502.28 g. ofcrystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g.of dyestuif, and 1.5 g. of titanium dioxide; and dried. The obtaineddrages each weigh 120 mg. and each contain 25 mg. of active substance.

(c) To produce 1000 capsules each containing 25 mg. of active substance,25 g. of 1-[2-[4-(8 chloro 10,11- dihydro 5Hdibenzo[a,d]cyclohepten-10-yl)1-piperazinylJ-ethyl]3-methyl-2-irnidazolidinoneare mixed with 248 g. of lactose; the mixture is then evenly moistenedwith an aqueous solution of 2.0 g. of gelatine, and granulated through asuitable sieve (e.g. sieve III, Ph. Helv. V). The granulate is mixedwith 10.0 g. of dried maize starch and 15.0 g. of talcum; it is thenevenly filled into 1000 hard gelatine capsules, size 1.

(d) A suppository foundation mixture is prepared from 2.5 g. of1-[2-[4-(8-methyl-l0,ll-dihydro-SH-dibenzo- [a,d] cyclohepten10-yl)-1-piperazinyl]-ethyl]-3-methyl- Z-imidazolidinone and 167.5 g. ofadeps solidus; from this mixture are poured 100 suppositories eachcontaining 25 mg. of active substance.

(e) A solution of 25 g. of l-[2-[4-(8-methyl-10,1l-di hydroSH-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]ethyl]-3-methyl-2-imidazolidinone-dihydrochloride in one litre of wateris filled into 1000 ampoules, and sterilized. An ampoule contains a 2.5%solution of 25 mg. of active substance.

The following examples further illustrate the production of the newcompounds of Formula I, and of intermediate products not describedhitherto; but these examples in no way limit the scope of the invention.The temperatures are given in degrees centigrade.

EXAMPLE 1 (a) A suspension of 11.7 g. (0.040 mole) of 8-methyl- 10(1-piperazinyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, 8.46 g.(0.044 mole) of l-(2-chloro-ethyl) -3- methyI-Z-imidazolidinone and 11.0g. (0.08 mole) of potassium carbonate in ml. of diethyl ketone isrefluxed for 24 hours. The reaction mixture is cooled and filtered offunder suction; the precipitate is then washed with acetone, and thefiltrate concentrated in vacuo. The residue is taken up in benzene andwater, the aqueous phase separated, and the organic phase extracted withl-n-methanesulphonic acid. The free base is precipitated withconcentrated ammonia from the acid extract, and the crude base taken upin benzene. The benzene solution is washed with water, dried overmagnesium sulphate, and concentrated by evaporation. The crystallineresidue is recrystallized from a little ethyl acetate/petroleum ether,whereupon the pure 1 [2-[4-(8-methyl-l0,l1-dihydro-5H-dibenzo[a,d]cyclohepten 10 yl)-1-piperazinyl]-ethyll-3- methyl-2-imidazolidinone hasa MP. of 116-117; yield 11.7 g., 70% of the theoretical value.

4.2 g. (0.01 mole) of the obtained free base are dissolved in 20 ml. ofanhydrous ethyl acetate; to this solution is then added a solution of2.32 g. (0.02 mole) of maleic acid in 10 ml. of anhydrous acetone. Anamount of 50 ml. of abs. ether is added and the precipitated bismaleatefiltered 011?: it is subsequently washed with absolute ether, and driedin vacuo. After recrystallization from a little ethanol/ethyl acetate,the pure 1-[2-[4-(8- methyl-10,11-dihydro 5H dibenzo[a,d]cyclohepten-10- yl)-1-piperazinyl]-ethyl] 3methyl-2-imidazolidinonebis-maleate melts at 138-140".

8-methyl-10-(l-piperazinyl) 10,11 dihydro-SH-dibenzo[a,d]cycloheptene,required as starting material, can be produced as follows:

(b) To a solution of 12.1 g. (0.05 mole) of 8-methyl- 10-chloro 10,11dihydro-SH-dibenzo[a,d]cycloheptene in 80 ml. of benzene are added 23.7g. (0.15 mole) of 1- piperazinecarboxylic acid ethyl ester; the solutionis then refluxed for 24 hours. The reaction mixture is poured into 200m1. of ice water; to this are added 25 ml. of 2-n sodium hydroxidesolution, and the benzene phase is separated. The aqueous phase isshaken out with benzene; the

7 organic phases are washed with water, dried over magnesium sulphate,the solvent is removed in vacuo, and the obtained crude residue furtherused.

(c) An amount of 12.9 g. of the crude product obtained according to (b)is dissolved in 50 ml. of abs. ethanol; to this solution are added 10 g.(0.15 mole) of potassium hydroxide, and the mixture is refluxed for 20hours. The reaction solution is cooled and concentrated in vacuo; wateris added to the residue and the base taken up in benzene. The benzenesolution is washed with water until neutral, and the acid aqueous phasemade alkaline with concentrated sodium hydroxide solution. The free baseis extracted with benzene; the benzene solution is washed with water,dried over magnesium sulphate, and dried in vacuo. The crystallineresidue is recrystallized from ethyl/ acetate/pentane. The pure8-methyl-10-(1-piperazinyl)- 10,1l-dihydro-SH-dibenzo[a,d]cycloheptenemelts at 95- 96; yield 4.4 g. 30% of the theoretical value; M.P. of thebis-methane sulphonate 194196.

EXAMPLE 2 (a) Analogously to Example 1 is obtained the following finalproduct:

From 11.7 g. (0.040 mole) of 8-methyl-10-(l-piperazinyl)-10,11-dihydro Hdibenzo[a,d]cycloheptene and 8.36 g. (0.044 mole) of1-(3-chloropropyl)-3-ethyl-2- imidazolidinone is obtained:1-[3-[4-(10,11-dihydro- SH-dibenzo[a,d]cyclohepten yl)-1-piperazinyl]-propyl]-3-ethyl 2 imidazolidinone; M.P. of the bismaleate, which isproduced analogously to Example 1a, is 113-115 yield 21.7 g.; 80% of thetheoretical value. The 1-(3-chloropropyl) 3 ethyl-2-imidazolidinone,

required as starting material, is produced as follows:

(b) An amount of 15.6 g. (0.175 mole) of 2-ethylaminoethanol isdissolved in 30 ml. of abs. methylene chloride. To this solution isadded dropwise at 5 to 0, in the course of 45 minutes, a solution of20.9 g. (0.175 mole) of 3-chloropropyl)-isocyanate in 20 ml. of abs.methylene chloride. The reaction mixture is stirred for 2 hours at 30,and then cooled to 0. To the cooled solution containing the crude1-ethyl-1-(Z-hydroxyethyl)-3-(3- chloropropyl)-urea is added dropwise,in the course of 30 minutes, a solution of 21.9 g. (0.182 mole) ofthionyl chloride in 20 ml. of abs. methylene chloride. The reactionmixture is afterwards refluxed for 4 hours, and concentrated in vacuo.The obtained residue: crude l-ethyl-l-(2-chloroethyl)-3-(3-chloropropyl)-urea, is dried under high-vacuum at70-80; yield 42.0 g. of crude product, which correspond to 39.8 g. (100%of the theoretical value) of pure compound.

(c) With the exclusion of moisture and whilst thorough stirring ismaintained, 42.0 g. of the crude urea derivative (obtained according to(b) containing 39.8 g. (0.175 mole) of pure compound are heated for 3hours in a bath at 120, and afterwards for 6 hours in a bath at 140. Theobtained crude 1 (3-chloropropyl)-3-ethyl-2-imidazolidinone is distilledunder high-vacuum; B.P. 101-103 0.01 Torr (n :1.4868); yield 28.1 g.,84.5% of the theoretical value.

EXAMPLE 3 (a) An amount of 11.9 g. (0.049 mole) of S-methyl-10-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene is dissolved in 50ml. of abs. benzene; this solution is then added dropwise at roomtemperature to a solution of 15.6 g. (0.073 mole) of1-[2-(1-piperaziny1)-ethyl]-3- methyl-2-imidazolidinone in 30 ml. ofabs. benzene; and the reaction mixture is refluxed for 20 hours. Thecooled solution is poured on to 200 ml. of ice water; to this are added20 ml. of 2-n sodium hydroxide solution, and the organic phase isseparated. The organic phase is washed with water, and extracted with150 ml. of l-n methanesulphonic acid solution. The pH of the aqueousextract is adjusted with concentrated sodium hydroxide solution to 13.The precipitated crude base is extracted with ben- Zene; the benzenesolution is washed with water, dried over magnesium sulphate, andconcentrated in vacuo. The residue is recrystallized from ethyl acetate/petroleum ether. The obtained pure 1-[2-[4-(8-methyl-10,1l-dihydro 5Hdiben'zo[a,dJcyclohepten-lO-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone melts at 116117.

The 8-methyl-10-chloro-10,11-dihydro 5H dibenzo- [a,d]cycloheptenerequired as starting material is produced as follows:

(b) An amount of 11.2 g. (0.05 mole) of 8-methyl-10, -11 dihydro 5Hdibenzo[a,d]cyclohepten-l0-ole is dissolved in 50 ml. of abs. benzene;to the solution are then added 5.14 g. (0.065 mole) of pyridine. To thissolution is then added dropwise at 5 a solution of 7.14 g. (0.06 mole)of thionyl chloride in 25 ml. of abs. benzene. The reaction mixture isstirred, whilst nitrogen is fed in, for 5 hours at 50; it is afterwardspoured into 200 m1. of ice water. The mixture is extracted withether/methylene chloride (2:1). The ether/methylene chloride solution iswashed with 1-n hydrochloric acid, 1-n sodium hydrogen carbonatesolution, and water; it is then dried over magnesium sulphate, andconcentrated in vacuo. The crystalline residue:8-methyl-10-chloro-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene, melts at-68; yield 11.3 g-, 93% of the theoretical value.

EXAMPLE 4 An amount of 2.92 g. (0.01 mole) of8-methyl-10-(1-piperazinyl) -10, 1l-dihydro-SH-dibenzo[a,d]cyclohepteneis refluxed with 2.80 g. (0.014 mole) of crude 1-methyl-3,3bis-(2-chloroethyl)-urea and 3.6 g. (0.026 mole) of anhydrous potassiumcarbonate in 36 ml. of diethyl ketone for 12 hours. A further 2.4 g.(0.018 mole) of potassium carbonate are added after 4 hours reactiontime, and the same amount is again added after 8 hours reaction time.The reaction mixture is cooled, diluted with ether, filtered, and thefiltrate concentrated in vacuo. The residue (5.22 g.) is taken up inether; the solution is then extracted with l-n hydrochloric acid, theacidified extract washed with ether, and excess sodium carbonate added.The precipitated free base is taken up in ether; the ether solution isthen washed with water, dried over sodium sulphate, and concentrated byevaporation. The residue is chromatographed on a column of silica gel(Merck, grain size 0.050.2 mm.), which has been impregnated with 0.5-nsodium hydroxide solution. Chloroform is used as the eluting agent. Thefractions containing the crude product are concentrated by evaporation.The residue is recrystallized from ethyl acetate/petroleum ether,whereupon the pure 1 [2 [4-(8-methyl-10,1l-dihydro-SH-dibenzo- [a,d]cyclohepten 10-yl -1-piperazinyl] -ethyl] -3 -methyl 2-amidazolidinonemelts at 116117, yield 2.72 g., 65% of the theoretical value.

EXAMPLE 5 Analogously to Example 1a the following end products areobtained:

(a) From 31.2 g. (0.1 mol) of 8-chloro-10-(1-piperazinyl)-10,1I-dihydro-SH-dibenzo [a,d] cycloheptene and 17.8 g. (0.11 mol) of1-(2-chloroethyl)-3-methyl-2-imidazolidinone, the 1-[2-[4-(8-chloro-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten 10 yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, M.P. 134-135 Yield: 33.6: of the theoreticalvalue.

M.P. of the bis-methanesulphonate, 1 /3 hydrate: 180 181 (fromethanol-diethylether) (b) From 31.2 g. (0.1 mol) of8-chloro-10-(1-piperazinyl)-10,1 l-dihydro-SH-dibenzo [a.d ]cyclohepteneand 20.9 g. (0.11 mol) of 1-(3-chloropropyl)-3-ethyl-2-imidazolidinone,the crude 1-[3-[4-(8-chloro-10,1l-dihydro- 5Hdibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-propyl]-3-ethyl-2-imidazolidinone, the bis-maleate of which [preparedaccording to Example 121)] melts at 113-115 (0) From 31.2 g. (0.1 mol)of 8-chloro-10-(1-piperazinyl) -10,1 l-dihydro-SH-dibenzo[a,dJcycloheptene and 24.0 g. (0.11 mol) of1-(3-chloropropyl)-3-buty1-2-imid- 9 azolidinone, the crude1-[3-[4-(8-chloro-10,1l-dihydro- 5H dibenzo[a,d1 cyclohepten10-y1)-1-piperazinyl]-propyl]-3-butyl-2-imidazolidinone. Yield: 35.6g.=73% of the theoretical value.

The product is an oily compound, which is dissolved in acetone, to whichan ethereal solution of hydrochloric acid is added until congo-acidreaction sets in. A solid precipitates which is filtered by suction andrecrystallized from ethanol/ethylacetate containing a small amount ofdiethylether, whereby the pure1-[3-[4-(8-chloro-10,1l-dihydro-SH-dibenzo [a,d] cycloheptenlO-yl-1-piperazinyl] propyl]-3-buty1-2-imidazolidinone-dihydrochloride isobtained as a two-third hydrate. M.P. 195-197".

The 1 (3-chloropropyl)-3-butyl-2-imidazolidinone required as startingmaterial may be prepared by the following procedure:

(d) 19.6 g. (0.175 mol) of Z-butyIamino-ethanol are dissolved in 30 ml.of absolute methylene chloride to which solution are dropped, at atemperature of from 5 to a solution of 20.9 g. (0.175 mol) of(ii-chloropropyl)-isocyanate in 20 ml. of absolute methylenechloride inthe course of 45 minutes. The reaction mixture is stirred at 30 for 2hours and then cooled to 0. Into the cooled solution containing thecrude 1-butyl-1-(2-hydroxyethyl)-3-(3-chloropropyl)-urea, a mixture of21.9 g. (0.182 mol) of thionylchloride in 20 ml. of absolutemethylene-chloride is dropped in the course of 30 minutes. The reactionmixture is then refluxed for 4 hours followed by evaporation under avacuum. The residue which represents the crudel-butyl-l-(2-chloroethyl)-3-(3-chloropropyl)- urea is dried at 70-80" ina high vacuum, then heated in a bath at 120 for 3 hours, followed byheating in a bath at 140 for 6 hours. The crude product is thendistilled in a high vacuum. B.P. 110-112/0.05 Torr.

EXAMPLE 6 Analogously to Example 1a the following final products may beprepared:

(a) From 27.8 g. (0.1 mol) of 10-(1-piperazinyl)-10,11-dihydro-SH-dibenzo [a,d]cycloheptcne and 17.8 g. (0.11 mol) of 1(2-chloroethyl)-3-methyl-Z-imidazolidinone, the 1- [2- [4- 10,1l-dihydro-SH-dibenzo [a,d] cyclohepten- 10yl)-l-piperazinyl]-ethyl]-3-methy1-Z-imidazolidinone. M.P. 117-118;Yield: 34.3 g.=85% of the theoretical value. The mono-maleate (fromethanol/diethylether) melts at 172-173.

(b) From 27.8 g. (0.1 mol) of 10-(1-piperazinyl)-l0,l1-dihydro-5H-dibenzo[a,d]cycloheptene and 22.4 g. (0.11 mol) of1-(2-chloroethyl)-3-butyl-2-imidazolidinone, the 1[2-[4-(10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-10- yl)-1-piperazinyl]-ethyl]-3-butyl-2-imidazolidinone. M.P. -8687. Yield:34.0 g.=76% of the theoretical value. The mono-maleate (fromethanol/diethylether) melts at 133- 134.

(c) From 27.8 g. (0.1 mol) of -(1-piperazinyl)-10,11- dihydro SH-dibenzo[a,d]cycloheptene and 20.9 g. (0.11 mol) of1-(3-chloropropyl)-3-ethyl-2-imidazolidine, the crude 1[3-[4-(10,1l-dihydro-SH-dibenzo[a,d]cyclohepten10-yl)-1-piperazinyl]-propyl]-3-ethyl-2-imidazolidinone. Yield: 33.7g.=78% of the theoretical value. The bis-maleate .l Vz hydrate preparedanalogously to Example 1a melts at 104-106".

EXAMPLE 7 Analogously to Example 1a, the following end products may beprepared:

(a) From 30.8 g. (0.1 mol) of crude 8-methoxy-10- (1 piperazinyl)10,1l-dihydro-SH-dibenzo[a,d]cycloheptene and 17.8 g. (0.11 mol) of1-(2-chloro-ethyl)-3- methyl-Z-imidazolidinone, the 1-[2-[4-(8-methoxy-10,1 1- dihydro 5H dibenzo[a,d]cyclohepten-10-y1)-1-piperzinyl]-ethyl]-3-methyl-Z-imidazolidinone. M.P. 122-123 (from ethylacetate/ petroleum ether). 3ield: 30.4 g. =70% of the theoretical value.The bis-maleate (from absolute ethanol/diethylether) melts at 144-146.

(b) From 30.8 g. (0.1 mol) of crude 8-methoxy-10- (1 piperazinyl)10,1l-dihydro-5H-dibenzo[a,d]cycloheptene and 19.4 g. (0.11 mol) of1-(3-chloropropyl)-3- methyl-2-imidazolidinone, the crude1-[3-[4-(8-methoxy- 10,11 dihydro 5H dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-l-propyl]3-methyl-2-imidazolidinone. Yield: 22.8 g.=62% ofthe theoretical value. The bis-maleate. hydrate (from absolute ethanol)melts at 106-108.

(c) The 8 methoxy-10'(1-piperazinyl)-l0,1l-dihydro-SH-dibenzo[a,d1cycloheptene required as starting material may beobtained by the following procedure:

48.0 g. (0.2 mol) of 8-methoxy-IO-hydroxy-SH-dibenzo [a,d]cyclohepteneare dissolved in 200 m1. of chloroform, 20.7 g. (0.26 mol) of pyridineare added to which solution, in the course of 45 minutes at 05, asolution of 28.4 g. (0.24 mol) of thionylchloride in m1. of benzene aredropped. The reaction mixture is stirred at 45-50" for 2 hours whilstnitrogen gas is fed in and subsequently poured into /2 litre of ice-Water.

After adding an amount of methylenechloride the organic layer isseparated and subsequently washed with 200 ml. of each 1-n.hyrdrochloric acid, water, saturated aqueous sodium hydrogencarbonatesolution and finally With water. The organic layer is separated, driedover magnesium sulphate and evaporated in vacuo, whereby the 8methoxy-10-chloro-10,11-dihydro-5H-dibenzo[a,d] cycloheptene isobtained. M.P. 84-86.

(d) 25.8 g. (0.1 mol) of the compound as prepared under (0) are refluxedtogether with 42.4 g. (0.3 mol) of l-piperazine carboxylic acid ethylester in 200 ml. of benzene for 24 hours. The mixture is then pouredinto 500 ml. of ice-water, 50 ml. of 2-n. sodium hydroxide solution areadded, and the benzene layer is separated. The aqueous phase isextracted with benzene, the combined benzene phases are washed withWater, dried over magnesium sulphate and evaporated in vacuo, whereby anoily residue is obtained. 38.0 g. of this crude product are dissolved in100 m1. of absolute ethanol and after adding 20.0 g. (0.358 mol) ofpotassium hydroxide refluxed for 20 hours. The solution is thenevaporated in vacuo and to the residue 200 ml. of each benzene, andwater, are added. The benzene layer is washed with water to neutral andextracted with 200 ml. of 2-n. hydrochloric acid, then the acid phase isrendered alkaline by means of concentrated sodium hydroxide solution,whereby a solid precipitates, which is extracted with benzene. Thecombined benzene extracts are thoroughly washed with water, dried overmagnesium sulphate and evaporated in vacuo to dryness.

The residue represents the 8methoxy-lO-(l-piperazinyl)-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene andis used in crude state for the subsequent reaction. Yield: 10.8 g.=35%of the theoretical value.

EXAMPLE 8 (a) Analogously to Example 121, 30.8 g. (0.01 mol) of crude 8methoxy-10-(l-piperazinyl)-10,11-dihydro-5-H- dibenzo[a,d]cycloheptene,obtained according to Example 7c and d respectively, and 21.0 g. (0.11mol of 1- (2 chloroethyl)-isopropyl-2-imidazolidinone are reacted toproduce 1-[2- [4-(8-methoxy-10,1 l-dihydro-SH-dibenzo [a,d]cyclohepten10 yl) l-piperazinyl]-ethlyl]-3-isopropyl Z-imidazolidinone. Yield. 35.6g.=77% of the theoretical value. M.P. of the bis-maleate. hydrate (fromabsolute ethanol/diethylether): -127".

The 1 (2-chloroethyl)isopropyl-Z-imidazolidinone required as startingmaterial may be obtained by the following procedure:

(b) 105.1 g. (1.0 mol) of freshly distilled diethanolamine are dissolvedin 1000 ml. of absolute methylenechloride to which solution, in thecourse of 1 hour, a solution of 89.5 g. (1.05 mols) ofisopropylisocyanate at a temperature of 0-5 is dropped. The reactionmixture is refluxed for 1 hour whilst stirring. After cooling to 0, a

11 solution of 250.0 g. (2.1 mols) of thionylchloride in 250 ml. ofabsolute methylenechloride is added dropwise at 5, in the course of 1hour. After refluxing for 4 hours the mixture is evaporated in vacuo.The residue which represents the crude1-isopropyl-3,3-bis-(2-chloroethyl)-urea is heated during 3 hours at 120with exclusion of moisture, followed by heating to 140 for 6 hours.

The product is fractionated in a high vacuum, whereby the pure1-(2-chloroethyl)-3-isopropyl-2-imidazolidinone distills at 88-90/ 0.02Torr; n =1.4855.

EXAMPLE 9 Analogously to Example 1a the following end products areobtained:

(a) from 29.2 g. (0.1 mol) of crude -methyl-10-(lpiperazinyl) 10,11dihydro 5H dibenzo[a,d]cycloheptene and 17.8 g. (0.11 mol) of1-(2-chloroethyl)-3- methyl 2 imidazolidinone, the crude1-[2-[4-(5-methyl- 10,11 dihydro 5H dibenzo[a,d]cyclohepten--yl)-1-piperazinyl] ethyl] 3 methyl 2 imidazolidinone. Yield: 32.6 g.=78% ofthe theoretical value. The dioxalate. /3 hydrate melts at 120125(precipitated from acetone/ethylacetate followed by recrystallizationfrom acetone containing a small amount of an ethanol-diethylethermixture.

(b) from 29.2 g. (0.1 mol) of crude S-methyl-lO-(lpiperazinyl) 10,11dihydro 5H dibenzo[a,d]cycloheptene and 19.4 g. (0.11 mol) of1(3-chloropropyl)-3- methyl 2 imidazolidinone, the crude1-[3-[4-(5-methyl- 10,11 dihydro 5H benzo[a,d]cyclohepten 10 yl)- 1piperazinylJ-propyl] 3 methyl 2 imidazolidinone. Yield: 35.2 g.=81.2% ofthe theoretical value. The pure oxalate melts at 162165 precipitatedfrom acetone/ ethylacetate followed by recrystallization from anacetone/ethanol/diethylether mixture.

The 5 methyl 10 (1 piperazinyl) 10,11 dihydro- SHdibenzo[a,d]cycloheptene is prepared in the following manner:

(0) 44.4 g. (0.2 mol) of 5-methyl 10,11 dihydro- 5Hdibenzo[a,d]cyclohepten 10 one are dissolved in 500 ml. of methanol towhich solution, during refluxing, a solution of 7.55 g. (0.2 mol) ofsodium borohydride in 80 ml. of Water is dropped in the course of 40minutes. Refluxing is then continued for 2 hours followed by evaporatingthe solvent in vacuo. The residue is poured into 200 ml. of ice-waterand this mixture is triturated with a 1-n. sodium-dihydrogenphosphatesolution and 1-n. hy drochloric acid until pH 7 is reached. The solutionobtained is extracted with a diethylether/methylenechloride mixture(2:1), the organic layers washed with water, dried over magnesiumsulphate and evaporated in vacuo. The residue thus obtained isrecrystallized from benzene/petroleum ether, whereby the pure5-methyl-10-hydroxy- 10,l1-dihydro-dibenzo[a,d]cycloheptene is obtained.M.P. 8990; Yield: 90% of the theoretical value.

(d) 40.3 g. (0.18 mol) of the compound prepared under (0) are dissolvedin 200 ml. of chloroform, together with 18.9 g. (0.234 mol) of pyridineto which solu tion, at a temperature of 0-5 a solution of 25.6 g. (0.216mol) of thionylchloride in 100 ml. of benzene is dropped. The reactionmixture is fed with nitrogen gas whilst stirring at 4550 for 2 hours,followed by pouring into 500 ml. of ice-water. Methylene chloride isadded and the organic layer is separated and subsequently washed with200 ml. of each of l-n. hydrochloric acid, water, saturated sodiumhydrogencarbonate solution and water until pH 7 is reached. The organiclayers are dried over magnesium sulphate and the solvents volatilized invacuo at 45. The oily residue represents the S-methyl 10 chloro 10,11-dihydro 5H dibenzo[a,d]cycloheptene which is used for the subsequentreaction. Yield: 43.5 g.=quantitative.

(e) 43.5 g. (0.18 mol) of this crude product and 85.5 g. (0.54 mol) ofl-piperazine carboxylic acid ethyl ester are dissolved in 400 ml. ofbenzene and refluxed for 20 hours. After cooling, the mixture is pouredinto 500 m1. of ice-water, ml. of 2-n. sodium hydroxide solution areadded, the benzene layer is separated and the aqueous phase is extractedwith benzene. The combined benzene extracts are washed with water, driedover magnesium sulphate and the solvent evaporated in vacuo, yielding anoily residue.

66.0 g. of this product are dissolved in 200 ml. of absolute ethanol andafter adding 40.0 g. of potassium hydroxide, the reaction mixture isrefluxed for 20 hours, followed by filtration of the warm reactionmixture from precipitated potassium carbonate. The filter-residue isWashed with warm ethanol and the combined filtrates are concentrated tosyrupy consistence, to which 300 ml. of each of benzene and water areadded. The benzene layer is separated, washed with water to neutralreaction, followed by extraction with 400 ml. of 2-n. hydrochloric acid.The acid solution is rendered alkaline by adding concentrated sodiumhydroxide solution, which is then extracted with benzene. The combinedbenzene layers are washed with water, dried over'magnesium sulphate andevaporated in vacuo to dryness.

The residue represents the 5-methyl-10-(1-piperazinyl)- 10,11 dihydro 5Hdibenzo[a,d] cycloheptene in crude state. Yield: 52.5 g.=40% of thetheoretical value.

EXAMPLE 10 Analogously to Example 1a the following end products areobtained;

(a) From 30.6 g. (0.1 mol) of crude 5,8 dimethyl- 10 (1 piperazinyl)10,11 dihydro 5H dibenzo- [a,dJcycloheptene and 17.8 g. (0.11 mol) of1-(2-chloroethyl) 3 methyl 2 imidazolidinone, the crude 1-[2- [4-(5,8dimethyl 10,11 dihydro 5H dibenzo[a,d] cyclohepten 10 yl) 1piperazinyl]-ethyl]-3-methyl- Z-imidazolidinone. Yield 30.2 g.=70% ofthe theoretical value. The dioxalate hydrate (precipitated fromacetone/diethylether is recrystallized from ethyl acetate containing asmall amount of an ethanol/diethylether mixture) melts at 162-168.

(b) From 30.6 g. (0.1 mol) of crude 5,8-dimethyl-10- (1 piperazinyl)10,11 dihydro 5H dibenzo[a,d]cycloheptene and 19.4 g. (0.11 mol) of1-(3-chloropropyl)- 3 methyl 2 imidazolidinone, the crude 1-[3-[4-(5,8-dimethyl 10,11 dihydro 5H dibenzo[a,d]cyclohepten 1O yl) -1piperazinyl]-pr0pyl] 3 methyl-2- imidazolidinone. Yield: 32.2 g.=72% ofthe theoretical value. The dioxalate. hydrate melts at 198-200".

The crude 5,8 dimethyl 10 (1 piperazinyl) 10,11- dihydro 5Hdibenzo[a,d]cycloheptene required as starting material may be preparedanalogously to Example 9c-e from 5,8 dimethyl 10,11 dihydro 5H dibenzo-[a,d]cyclohepten l0 one (M.P. 99 from diethylether) via the followingintermediate compounds:

(c 5,8 dimethyl 10 hydroxy 10,11 dihydro-5H- dibenzo[a,d]cycloheptene;M.P. 87-94 (from methylcyclohexane/pentane),

(c 5,8 dimethyl 1O chloro 10,11 dihydro 5H- dibenzo[a,d]cycloheptene ascrude product.

EXAMPLE 11 Analogously to Example 4 the following final products areobtained:

(a) From 3.1 g. (0.01 mol) of 8-chloro-l0-(1-piperaz1nyl)-10,ll-dihydro-SH-dibenzo [a,d] cycloheptene and 2.80 g. (0.014 mol) ofl-methyl-3,3-bis-(2-chloroethyl)- urea, the1-[2-[4-(8-chloro-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-10-yl) 1piperazinyl]ethyl]-3-methyl-2- imidazolidinone. M.P. 134-135 Yield: 2.4g.=60% of the theoretical value.

(b) From 2.7 g. (0.01 mol) of l0-(1-piperazinyl)-10,ll-dihydro-SH-dibenzo[a,d]cycloheptene and 2.80 (0.014 mol) of1-methyl-3,3-bis-(2-chloroethyl)-urea, the 1-[2-[4-(10,11-dihydro 5Hdibenzo[a,d]cyclohepten- 10-yl) l-piperazinyl] -ethyl] -3methyl-Z-imidazolidinone.

13 M.P. 117-118"; Yield: 2.82 g.=70% of the theoretical value.

(c) From 3.08 g. (0.01 mol) of crude 8-methoxy-10-(l-piperazinyl)-l0,ll-dihydro 5H dibenzo[a,d]cycloheptene and 2.80 g.(0.014 mol) of 1-methyl3,3-bis-(2- chloroethyl)-urea, the1-[2-[4-(8-methoxy-10,11-dihydro-SH-dibenzo[a,d]-cyclohepten10-yl)-1-piperazinyl]- ethyl]-3-methyl-2-imidazolidinone. M.P. l22l23(from ethylacetate/petroleum ether). Yield: 2.95 g.=68% of thetheoretical value.

(d) From 2.92 g. (0.01 mol) crudeS-methyl-lO-(lpiperazinyl)-l0,1l-dihydro 5H dibenzo[a,d]cycloheptene and2.8 g. (0.014 mol) of 1-methyl-3,3-bis-(2-chloroethyl)-urea, the crude1-[2-[4-(5-methyl-10,1l-dihydro-SH-dibenzo [a,d] cyclohepten 10-yl-1-piperazinyl]- ethyl]-3-methyl-2-imidazolidinone, which is convertedby oxalic acid into the di-oxalate. Va hydrate. M.P. 120- 125 fromethylacetate/ethanol/diethylether.

(e) From 3.06 g. (0.01 mol) of 5,8-dimethyl-10-(1-piperazinyl)-10,l1-dihydro 5H dibenz[a,d]cycloheptene and 2.80 g. (0.014mol) of 1-methyl-3,3-bis-(2- chloroethyl)-urea, the crude1-[2-[4-(5,8-dimethy1-10,11- dihydro-SH-dibenzo[a,d]cycl0hepten10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, the oxalate.hydrate of which melts at 162-168.

EXAMPLE 12 Analogously to Example 4 the following end product isobtained:

(a) From 3.08 g. (0.01 mol) crude S-methoxy-lO-(lpiperazinyl)-10,l1dihydro-SH dibenzo[a,d]cycloheptene and 3.18 g. (0.014 mol) ofl-isopropyl-3,3-bis-(2- chloroethyl)-urea, the1-[2-[4-(8-methoxy-10,ll-dihydro-H-dibenzo[a,d] cyclohepten-lO-yl) 1piperazinyl1- ethyl]-3-isopropyl-2-imidazolidinone. Yield: 2.92 g. Thebis-maleate. hydrate (precipitated from an acetone/ diethylethersolution followed by recrystallization from ethanol/diethylether) meltsat 125-127.

The 1-isopropyl-3,3-bis-(2-chloro-ethyl)-urea required as startingmaterial is prepared by the following method:

(b) To a solution of 10.5 g. (0.1 mol) of freshly distilled diethanolamine in 100 ml. of absolute methylenechloride a solution of 8.95 g.(0.105 mol) of isopropylcyanate in 20 ml. of absolute methylene chlorideis dropped, at a temperature of 05 in the course of 30 minutes, followedby stirring each for one hour at ambient temperature and then byrefluxing. After cooling to 0, a solution of 25.0 g. (0.21 mol) ofthionylchloride in absolute methylenechloride at a temperature of 0-5 isadded dropwise and then the mixture is refluxed for 4 hours, evaporatedin vacuo to dryness and dried at 40 in a high 'vacuum. The1-isopropyl-3,3-bis-(2-chloroethyl)-urea is obtained as an oily product.

EXAMPLE 13 Analogously to Example 4 the following end product isobtained:

(a) From 2.7 g. (0.01 mol) of -(1-piperazinyl)-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene and 3.37 g. (0.014 mol) of1-buty1-3,3-bis-(2-chloroethyl)-urea, the 1-[2-[4-(10,11-dihydro 5Hdibenzo[a,d]cyclohepten- 10-y1)-1-piperazinyl]-ethyl]3-butyl-2-imidazolidinone. M.P. 86-87 (from ethylacetate/petroleumether); Yield: 2.99 g.=62% of the theoretical value.

The 1-butyl-3,3-bis-(2-chloroethyl)-urea is prepared analogously toExample 12b.

(b) From 10.5 g. (0.1 mol) of freshly distilled dieth anolamine, 10.4 g.(0.105 mol) of butylisocyanate and 25.0 g. (0.21 mol) ofthionylchloride. The 1-butyl-3,3-bis- (2-chloroethyl)-urea is obtainedas an oily product which is used for subsequent reaction.

EXAMPLE l4 Analogously to Example 3a the following final products areprepared:

(a) From 13.2 g. (0.05 mol) of 8,10-dichloro-10,11-

14 dihydro-SH-dibenzo[a,d]cycloheptene and 15.9 g. (0.075 mol) of1-[2-(1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone, the 1-[2-[4-(8-chloro10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl] 3-methyl-Z-imidazolidinone. M.P. 134-135 Yield: 6.55 g.=30% of the theoreticalvalue. The bis-methanesulphonate. 1V3 hydrate melts at -181 (fromethanol/diethylether).

(b) From 11.4 g. (0.05 mol) of10-chloro-10,11-dihydro-SH-dibenzo[a,d]cycloheptene and 15.9 g. (0.075mol) of 1-[2-(1-piperazinyl) ethyl]-3-methyl-2-imidazolidinone, thel-[2-[4-(10,11 dihydro-SH-dibenzo [a,d]cyclohepten-10-yl)-1-piperazinyl]ethyl 3-methyl- Z-imidazolidinone. M.P. 112-418; Yield: 9.3 g.=46% ofthe theoretical value. The mono-maleate melts at 122- 123 (fromethanol/diethylether).

(c) From 12.9 g. (0.05 mol) of crude 8methoxy-l0- chloro-10,11-dihydro5H dibenzo [a,d]cycloheptene and 15.9 g. (0.075 mol) ofl-[2-(1-piperazinyl)-ethyl]-3- methyl-Z-imidazolidinone, the1-[2-[4-(8-methoxy-10,11- dihydro-5H-dibenzo[a,d]cyclohepten 10 yl) 1piperazinyl]-ethyl]-3-methyl-2-imidazolidinone. M.P. 122123; Yield: 8.7g.=48% of the theoretical value. The bismaleate melts at 144146 (fromethanol/diethylether).

(d) From 13.2 g. (0.05 mol) of 8,10-dichloro-10,11- dihydro 5Hdibenzo[a,d]cycloheptene and 18.0 g. (0.075 mol)1-[3-(l-piperazinyD-propyl]-3-ethyl-2-imidazolidinone, the crude1-[3-[4-(8-chloro-10,1l-dihydro- SH-dibenzo[a,d]-cyclohepten 10 yl) 1-piperazinyl]- propyl] 3 ethyl-Z-imidazolidione. Yield: 7.7 g. =33% ofthe theoretical value. The bis-maleate melts at 113- 115 (from absoluteethanol/diethylether).

(e) From 11.4 g. (0.05 mol) ofl0-chloro-10,11-dihydro-SH-dibenzo[a,d]cycloheptene and 18.0 g. (0.075mol) of 1-[3-(l-piperazinyl)-propyl] 3 ethyl2-imidazolidinone, the crude1-[3-[4-(10,ll-dihydro-dibenzo- [a,d]cyclohepten-l0 yl) F 1piperazinyl]-propyl]-3-ethyl- Z-imidazolidinone. Yield: 10.4 g.=48% ofthe theoretical value. The bis-maleate. /2 hydrate melts at 104-106(from acetone and a small amount of ethanol/diethylether).

(f) From 12.9 g. (0.05 mol) of 8-methoxy-1O-chl0ro-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene and 17.0 g. (0.075 mol) of1-[3-(l-piperazinyl)-propyl]-3-methyl-2- imidazolidinone, the crude1-[3-[4-(8-methoxy-10,1l-dihydro 5H- dibenz0[a,d]-cyclohepten 10yl)-l-piperazinyl]-propyl]-3-methyl-2-imidazolidinone. Yield: 9.65g.=43% of the theoretical value. The bis-maleate. hydrate melts at106108 (from ethanol/diethylether).

(g) From 11.4 g. (0.05 mol) of10-chloro-10,l1-dihydro-SH-dibenzo[a,d]cycloheptene and 19.0 g. (0.075mol) of 1- [2- l-piperazinyl) -ethyl] -3-butyl-2-imidazo1idinone, the1-[2-[4-(10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-lO-yl) 1 piperazinyl]ethyl]-3-butyl-2-imidazolidinone. M.P. 86-87 (fromethylacetate/petroleum ether). Yield: 8.9 g.=40% of the theoreticalvalue.

EXAMPLE 15 Analogously to Example 3a the following end product isobtained:

(a) From 13.2 g. (0.05 mol) of 8,10-dichloro-10,l1-dihydro-SH-dibenzo[a,d]cycloheptene and 20.1 g. (0.075 mol) of1-[3-(1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone, the crude1-[3[4-(8-chloro-10,1l-dihydro-SH- dibenzo[a,d]cyclohepten-lO-yl)-1-piperazinyl]-propyl]- 3-butyl-2-imidazolidinone.Yield: 7.65 g.=31% of the theoretical value. The dihydrochloride.hydrate melts at 197 (from ethanol/ethylacetate/diethylether).

The 1- [3- l-piperazinyl) -propyl]-3-butyl-2-imidazolidinone required asstarting material is prepared by the following procedure:

(b) To a solution of 218.0 g. (1.0 mol) of1-(3-chloropropyl)-3-butyl-2-imidazolidinone prepared according toExample 5d and 175.0 g. 1.1 mols) of l-piperazine carboxylic acid ethylester in 1000 ml. of diethylketone are added 304.0 g. (2.0 mols) ofpotassium carbonate and the reaction mixture is refluxed for 24 hours,which mixture is then warm filtered. The residue is boiled two timeswith 500 ml. of chloroform and filtered. The com bined filtrates areevaporated in vacuo to dryness and the oily residue is fractioned in ahigh-vacuum. The pure 1- [3-(4ethoxycarbonyl 1piperazinyl)-propyl]-3-butyl- Z-imidazolidinone distills at 180210/0.01torr; n =1.4946. Yield: 266.0 g.=78% of the theoretical value.

340.4 g. (1.0 mol) of 1-[3-(4-ethoxycarbonyl)-1-piperazinyl)-propyl]-3-butyl-2-imidazolidinone are added to a solutionof 300.0 g. of potassium hydroxide in 1500 ml. of absolute ethanol andthe mixture is refluxed for 16 hours. The precipitate is filtered ofl?and washed with Warm ethanol. The combined filtrates are concentrated invacuo and the residue is triturated with 1000 m1. of benzene and 300 ml.of water. The aqueous phase is separated, saturated with potassiumcarbonate and extracted four times with benzene.

The combined benzene solutions are dried over potassium carbonate andthe solvent volatilized in vacuo. The residue is fractionated in ahigh-vacuum, whereby the pure 1-[3-(l-piperazinyl)-propyl]-3-butyl-2-imidazolidinone distills atl45l50/0.01 torr. n =1.5006; Yield: 250.0 g.=93% of the theoreticalvalue.

EXAMPLE 16 Analogously to Example 3a the following end product isobtained:

(a) From 12.9 g. (0.05 mol) crude8-methoxy-10-chloro-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene and 18.0g. (0.075 mol) of 1-[2-(l-piperazinyl)-ethyl]-3-is0propyl-Z-imidazolidinone, the crude 1-[2-[4-(8-methoxy-l0,l1-dihydro Hdibenzo[a,dl-cyclohepten-lO-yl) 1piperazinyl]-ethyl]-3-isopropyl-2-imidazolidinone. Yield: 10.1 g.=44% ofthe theoretical value. The bis-maleate. hydrate melts at 125-127 (fromabsolute ethanol/diethylether).

The l[2-(l-piperazinyl)-ethyl] 3 isopropyl-Z-imidazolidinone is preparedanalogously to Example 15b and c.

(b) 190.6 g. (1.0 mol) of1-(2-chloroethyl)-3-isopropyl-2-imidazolidinone [prepared according toExample 81)] are reacted with 175.0 g. (1.1 mols) of l-piperazinecarboxylic acid ethyl ester yielding1-[2-(4-ethoxycarbonyl-l-piperazinyl)ethyl]-3-isopropyl 2imidazolidinone as crude product which is subsequently fractionated in ahigh vacuum, whereby impurities distill over in the range of from140190/0.01 Torr. The residue is then saponified and gives, finally, the1-[2-(1-piperazinyl)- ethyl]-3-isopropyl-Z-imidazolidinone. B.P.150-155/0.01 Torr; n =1.5034. Yield: 73% of the theoretical value.

EXAMPLE l7 Analogously to Example 3a the following end products areprepared:

(a) From 12.1 g. (0.05 mol) of crude S-methyl-lO- chloro 10,11 dihydro5H-dibenzo[a,d]cycloheptene [prepared according to Example 9d] and 15.9g. (0.075 mol) of 1 [2 (1 piperazinyl)-ethyl]-3-methyl-2-imadazolidinone, the crude 1 [2 [4 (5 methyl-10,11- dihydro 5Hdibenzo[a,d]cyclohepten yl)-1-piperazinyl] ethyl] 3 methyl 2imidazolidinone. Yield: 7.2 g.=37% of the theoretical value. Thedioxalate. hydrate melts at 120 125" (from ethyl acetate and a smallamount of ethanol/diethylether).

(b) From 12.1 g. (0.05 mol) of crude S-methyl-IO- chloro 10,11 dihydro5H-dibenzo[a,d]cycloheptene [prepared according to Example 9d] and 17.0g. (0.075 mol) of 1 [3 (1 piperazinyl)-propyl]-3-methyl-2-imidazolidinone, the crude 1 [3 [4 (5-methyl-l0,l1-

dihydro 5H dibenz0[a,d] cyclohepten 10 yl)-l-piperazinyl]-propyl] 3methyl 2 imidazolidinone. Yield: 7.55 g.=35% of the theoretical value.The dioxalate melts at 162-16S (from absolute ethanol/diethylether).

(c) From 12.8 g. (0.05 mol) of crude 5,8 dimethyl- IO-chloro 10,11dihydro 5H dibenzo[a,d]cycloheptene and 15.9 g. (0.075 mol) of 1 [2 (1piperazinyl) ethyl] 3 methyl-Z-imidazolidinone, the crude 1 [2 [4 (5,8dimethyl-l0,1l-dihydroJH-dibenzo- [a,d]cyclohepten l0 yl) 1piperazinyl]-ethyl]-3- methyl-2-imidazolidinone. Yield: 6.9 g.'=32% ofthe theoretical value. The dioxalate. hydrate melts at 162-l68 (fromethanol/ethylacetateldiethylether) (d) From 12.8 g. (0.05 mol) of crude5,8 dimethyl- 10 chloro 10,11 dihydro 5H dibenzo[a,d]cycloheptene and17.0 g. (0.075 mol) of 1 [3 (l-piperazinyl) propyl] 3 methyl 2imidazolidinone, the crude 1 [3 [4(5,8-dimethyl-10,ll-dihydro-SH-dibenzo[a,d] cyclohepten 10 yl)1piperazinyl]-propyl]- 3 methyl 2 imidazolidinone. Yield: 8.5 g.=38% 0fthe theoretical value. The dioxalate. hydrate melts at 198-200 (from alittle absolute ethanol/ethylacetate/ diethylether) What is claimed is:

1. A pharmaceutical composition comprising central nervous systemdepressant amount of a compound of the formula wherein X is hydrogen,chloro, methyl or methoxy;

R is alkyl having from one to four carbon atoms;

R is hydrogen or methyl; and

n is the integer 2 or 3; and the pharmaceutically acceptable acidaddition salt thereof or a pharmaceutical carrier therefor.

2. The composition of claim 1 with 1 [2 [4 (8- methyl-10,l1-dihydro 5Hdibenzo[a,d]cyclohepten-IO- yl)-l-piperazinyH-ethyl] 3methyl-2-imidazolidinone, and a pharmaceutically acceptable acidaddition salt thereof.

3. The composition of claim 1 with 1 [2 [4-(8- chloro 10,11 dihydro 5Hdibenzo[a,d]cyclohepten- 10 yl) 1 piperazinyl] ethyl] 3methyl-Z-imidazolidinone, and a pharmaceutically acceptable acidaddition salt thereof.

4. The method of producing a depressant eifect on the central nervoussystem of a warm-blooded animal comprising administering to said animalcentral nervous system depressant amount of a compound according to caim 1.

References Cited UNITED STATES PATENTS 3,699,107 10/ 1972 Schindler etal 424-250 3,707,562 12/ 1972 Schindler et al. 424-250 FOREIGN PATENTS1,093,910 12/1967 Great Britain.

STANLEY J. FRIEDMAN, Primary Examiner

